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3-vinyl-quinoxaline-2(1H)-one derivatives acting on FGFR-1, preparation method and uses thereof

A technology of FGFR-1 and methylquinoxaline, which is applied to medical preparations containing active ingredients, drug combinations, and pharmaceutical formulas, etc., can solve problems such as poor selectivity, low affinity, weak inhibition strength, etc., and achieve good safety Effect

Active Publication Date: 2015-09-09
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] One of the main purposes of the present invention is to solve the problems of poor selectivity, low affinity and low inhibitory strength of existing compounds to FGFR-1, and then provide a 3-vinyl-quinoxaline-2 that acts on FGFR-1 (1H)-ketone derivatives and their preparation methods and applications

Method used

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  • 3-vinyl-quinoxaline-2(1H)-one derivatives acting on FGFR-1, preparation method and uses thereof
  • 3-vinyl-quinoxaline-2(1H)-one derivatives acting on FGFR-1, preparation method and uses thereof
  • 3-vinyl-quinoxaline-2(1H)-one derivatives acting on FGFR-1, preparation method and uses thereof

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Experimental program
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Effect test

Embodiment 1

[0036] Embodiment 1: the synthesis of compound

[0037]

[0038] It can be seen from 1 and 2 that 1 is the synthesis route of compounds Kj1, Kj4, Kj5, and Kj6 of the present invention and 2 is the synthesis route of compounds Kj2 and Kj3. Wherein i: pyruvic acid, n-butanol, reflux; ii: acetic anhydride, piperidine, reflux; iii: anhydrous acetone, benzyl bromide, anhydrous potassium carbonate, reflux; iv: pyruvic acid, ethanol; v: acetic anhydride , piperidine, reflux.

[0039] 1, Synthesis of 3-methylquinoxalin-2(1H)-one

[0040] O-phenylenediamine (1.00 g, 9.25 mmol) and pyruvic acid (11 mmol) were dissolved in hot n-butanol (35 mL) and heated to reflux. The reaction was stirred for 3 hours, and a large amount of flocculent products precipitated out, and the mixture was cooled to room temperature. Suction filtration, washing with n-hexane 2-3 times to obtain crude 1-hydrogen 3-methylquinoxalin-2(1H)-one. The crude product was purified by recrystallization from ethanol ...

Embodiment 2

[0057] Example 2 Antitumor Activity Detection of Compounds

[0058] MTT is a yellow compound that accepts hydrogen ions. It can act on the respiratory chain in the mitochondria of living cells. The succinate dehydrogenase in the mitochondria of living cells reduces it to produce a water-insoluble blue-purple crystalline formazan. And deposited in cells, and dead cells do not have this function. DMSO can dissolve formazan in cells, and use an enzyme-linked immunosorbent assay to measure its light absorption value at a specific wavelength. Within a certain range of cell numbers, the amount of formazan formed is proportional to the number of cells, so it can indirectly reflect the number of living cells. quantity.

[0059] Cell culture: H460, Hct116, and normal liver cells HL7702 were cultured in RPMI 1640 medium containing 10% fetal bovine serum; Hela229 and B16-F10 were cultured in DMEM high-glucose medium containing 10% fetal bovine serum. The culture conditions were 37°C, 5...

Embodiment 3

[0072] Example 3 Kinase inhibitory activity assay

[0073] Using LANCE Ultra TR-FRET Assays, the FGFR-1 inhibitory activity of the six synthesized compounds was detected in vitro, and TKI258 was used as a positive control to test the IC of the compounds acting on FGFR-1 kinase 50 value.

[0074] Inhibition experiment of synthesized compounds on FGFR-1 kinase

[0075] (1) Prepare 1x kinase reaction buffer (50mM HEPES, pH 7.5; 0.01% Tween-20; 10mM MgCl2; 2mM DTT; 1mMEGTA), 1x LANCE Detection Buffer and kinase reaction termination solution (40mM EDTA).

[0076] (2) Preparation of compounds for kinase experiments: final dilution of compounds to 400 μM, 40 μM, 4 μM, 0.4 μM and 0.04 μM with 100% DMSO and 1× kinase buffer.

[0077] (3) Kinase reaction: Add FGFR-1 enzyme to 1x kinase buffer to prepare 4x enzyme solution. Prepare 2x peptide solution by adding ATP and ULight-JAK-1peptide to 1x kinase buffer. Add 2.5 μl 4x enzyme solution prepared above to each well and incubate at roo...

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Abstract

The present invention discloses 3-vinyl-quinoxaline-2(1H)-one derivative acting on FGFR-1, a preparation method and uses thereof, and belongs to the field of pharmaceutical chemistry. According to the present invention, o-phenylenediamine and pyruvic acid are adopted as raw materials and are subjected to cyclization to obtain 3-methyl quinoxaline-2(1H)-one, the 3-methyl quinoxaline-2(1H)-one reacts with different substituted aldehydes to obtain 3-substituted quinoxaline derivatives, and the 3-substituted quinoxaline derivatives are adopted as the intermediate products and are subjected to substitution to obtain other types of the target compounds, wherein the 6 new compounds are prepared; and the 3-vinyl-quinoxaline-2(1H)-one derivatives of the present invention have a certain inhibition effect for experiment cells, show a certain anti-tumor activity, and further have characteristics of cell selectively, good safety, and kinase inhibition activity.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a 3-vinyl-quinoxalin-2(1H)-one derivative acting on FGFR-1, a preparation method and application thereof. Background technique [0002] Malignant tumor is a common and frequently-occurring disease that seriously threatens human health. Traditional chemotherapy drugs have shown good anti-tumor effects, but their selectivity is low, they have strong side effects, and they are prone to drug resistance. The clinical application of drugs, so the target of new anti-tumor drugs has become a hot spot for scientific researchers. In recent years, the pharmaceutical industry has shown increasing interest in the field of receptor tyrosine kinases (RTKs), which play important roles in proliferation, motility and differentiation. The enhancement or overexpression of RTK activity is closely related to the occurrence of various cancers, so the development of selective tyrosine kina...

Claims

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Application Information

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IPC IPC(8): C07D401/06C07D241/44A61K31/498A61P35/00
CPCC07D241/44C07D401/06
Inventor 叶发青俞淑芳陈弟王宇谢自新梁广李校堃王跃武陈梁芳宋晓琴刘志国林丹
Owner WENZHOU MEDICAL UNIV
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